Ulcerative colitis (UC) is a form of inflammatory bowel disease (IBD) associated with the large intestine (colon) and its frequency in developed countries has been increasing since the mid 20th century (Danese et al. (2011) N. Engl. J. Med., 365:1713-25). The highest incidence and prevalence of IBD is seen in the populations of Northern Europe and North America and the lowest in Asia. A Westernized environment and lifestyle is linked to the appearance of IBD, which is associated with smoking, diets high in fat and sugar, medication use, stress, and high socioeconomic status. The incidence of UC is 1.2 to 20.3 cases per 100,000 persons per year, and its prevalence is 7.6 to 246.0 cases per 100,000 per year (Danese et al. (2011) N. Engl. J. Med., 365:1713-25). People with UC are at much above average risk of developing colorectal cancer (Eaden et al. (2001) Gut 48:526-35). The colorectal cancer risk is as high as 18% with 30 years of UC. The increased risk of colorectal cancer is due in part to inflammation-induced loss of barrier function. As yet, the causative agent for UC is not known. UC is considered a complex multifactorial disease and it has been hypothesized that autoimmunity, altered microbiome, mucosal barrier compromise and mucosal immunity and genetic factors plays a key role in this disease (Danese et al. (2011) N. Engl. J. Med., 365:1713-25).
UC is associated with defects in intestinal barriers that rely upon cellular tight junctions (TJs) (Das et al. (2012) Virchows Arch. 460:261-70). Identifying genes and proteins that could be targeted to enhance TJs and improve barrier function may lead to new treatment strategies for UC. TJ function may act as a disease modifier in IBD in general. While TJ compromise in the mouse is insufficient to cause intestinal disease, it can drive mucosal immune responses and accelerate the onset and severity of immune-mediated colitis once induced (Su et al. (2009) Gastroenterology 136:551-63). By preventing luminal antigens or infectious microbes from entering the stroma, TJs block unregulated inflammation. Indeed, through their ability to selectively determine intestinal permeability, TJ strongly influence gut physiology and pathophysiology (Madara, J. L. (1998) Annu. Rev. Physiol., 60:143-59).
As yet there are no powerful drugs or therapies to effectively protect against UC. The inflammatory cytokines, TNF-alpha and IFN-gamma, are elevated in ulcerative colitis. While anti-inflammatory drugs and immune suppressors (e.g., TNF alpha inhibitors) are currently prescribed for colitis treatment, side-effects such as risk of opportunistic infections, and the lack of efficacy in certain individuals, limit the quality of treatment (Yapal et al. (2007) Ann. Gastroenterology 20:48-53). Hence there is a need to develop additional immunotherapies to provide protection against colitis.